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Ledipasvir with Sofosbuvir Narrow Therapeutic Index, Such As Dabigatran, Should Be Used with Caution

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Ledipasvir with Sofosbuvir Narrow Therapeutic Index, Such As Dabigatran, Should Be Used with Caution VOLUME 38 : NUMBER 6 : DECEMBER 2015 NEW DRUGS Japanese trial of patients who were intolerant to likely to have a sustained response after 12 weeks of or ineligible for interferon, 10 patients discontinued daclatasvir and sofosbuvir compared to those who did because of elevations in liver enzymes and one not have cirrhosis. This combination was not assessed because of myasthenia gravis.6 When peginterferon in patients with genotype 1 disease and cirrhosis. The and ribavirin were added to daclatasvir and combination of daclatasvir and asunaprevir (with or asunaprevir, 18 patients discontinued. The most without peginterferon and ribavirin) was effective in a common reasons were rash, malaise, neutropenia and range of patients with genotype 1 or 4 infection. vertigo (2 cases of each).7 Daclatasvir regimens were generally well tolerated but Cardiac arrhythmias, including severe bradycardia, prescribers should be mindful of adverse reactions to have been reported in patients taking amiodarone other drugs in the treatment regimen. As daclatasvir with daclatasvir and sofosbuvir, so close monitoring is is metabolised by CYP3A4, there are numerous recommended with this combination. drug interactions that need to be considered. Most Daclatasvir should not be used in pregnancy. In animal importantly, concomitant use of strong CYP3A4 studies, it has been shown to cross the placenta, inducers is contraindicated as this may reduce the and maternal and embryofetal toxicity have been efficacy of daclatasvir. observed at high doses. Contraception should be T T manufacturer provided additional useful used during treatment and for five weeks afterwards. information Daclatasvir is also excreted in milk and breastfeeding REFERENCES † is not recommended. 1. Thompson A, Holmes J. Treating hepatitis C – what’s new. The safety and efficacy of daclatasvir in people Aust Prescr 2015. Epub ahead of print. who are co-infected with hepatitis B have not been 2. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, et al.; AI444040 Study Group. established as these patients were generally excluded Daclatasvir plus sofosbuvir for previously treated or untreated from the trials. chronic HCV infection. N Engl J Med 2014;370:211-21. 3. Nelson DR, Cooper JN, Lalezari JP, Lawitz E, Pockros PJ, Resistance to daclatasvir can occur. If patients Gitlin N, et al.; ALLY-3 Study Team. All-oral 12-week experience an increase in viral RNA during treatment, treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III the regimen should be discontinued. study. Hepatology 2015;61:1127-35. 4. Wyles DL, Ruane PJ, Sulkowski MS, Dieterich D, Drug interactions Luetkemeyer A, Morgan TR, et al.; ALLY-2 Investigators. Daclatasvir plus sofosbuvir for HCV in patients coinfected Daclatasvir is mainly metabolised by cytochrome with HIV-1. N Engl J Med 2015;373:714-25. 5. Manns M, Pol S, Jacobson IM, Marcellin P, Gordon SC, P450 (CYP) 3A4. It is contraindicated in combination Peng CY, et al.; HALLMARK-DUAL Study Team. All-oral with strong inducers of CYP3A4 (e.g. phenytoin, daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. carbamazepine, rifampicin, dexamethasone and Lancet 2014;384:1597-605. St John’s wort), as these drugs may lower daclatasvir 6. Kumada H, Suzuki Y, Ikeda K, Toyota J, Karino Y, Chayama K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype exposure. The daily daclatasvir dose should be 1b infection. Hepatology 2014;59:2083-91. increased to 90 mg with moderate CYP3A4 7. Jensen D, Sherman KE, Hézode C, Pol S, Zeuzem S, de Ledinghen V, et al.; HALLMARK-QUAD Study Team. inducers. Conversely, the dose should be reduced Daclatasvir and asunaprevir plus peginterferon alfa and to 30 mg per day with strong CYP3A4 inhibitors ribavirin in HCV genotype 1 or 4 non-responders. J Hepatol 2015;63:30-7. (e.g. clarithromycin, boceprevir, telaprevir, atazanavir, ritonavir, ketoconazole). First published online 1 October 2015 As daclatasvir inhibits P-glycoprotein, co-administered digoxin and other P-glycoprotein substrates with a Ledipasvir with sofosbuvir narrow therapeutic index, such as dabigatran, should be used with caution. Care is also urged with the Approved indication: hepatitis C statins as rosuvastatin concentrations are increased Harvoni (Gilead) with daclatasvir. 90 mg/400 mg tablets Conclusion Australian Medicines Handbook section 5.5 In general, daclatasvir-containing regimens were Sofosbuvir (Aust Prescr 2014;37:177-8) is a nucleotide very effective at clearing hepatitis C virus in patients analogue antiviral drug that is used in combination with chronic disease. This included those who had with other drugs to treat chronic hepatitis C. As the not adequately responded to previous treatments effectiveness of regimens containing interferon can be and patients who were co-infected with HIV. With limited by adverse effects, there is interest in studying the daclatasvir and sofosbuvir combination, adding other drugs to use in combination with sofosbuvir. ribavirin did not seem to give further benefit. Patients Ledipasvir is an antiviral drug aimed at a protein with genotype 3 infection who had cirrhosis were less (NS5A) in the hepatitis C virus. As this protein is Full text free online at www.australianprescriber.com 219 VOLUME 38 : NUMBER 6 : DECEMBER 2015 NEW DRUGS involved in viral replication, ledipasvir will reduce The ION-3 trial assessed the efficacy of a shorter the amount of virus in infected patients. Ledipasvir treatment regimen in previously untreated patients is rapidly absorbed. As the solubility of ledipasvir is without cirrhosis. It randomised 647 patients to take the pH-dependent, antacids, proton pump inhibitors and combination of ledipasvir and sofosbuvir, with or without H2-receptor antagonists can decrease absorption. ribavirin, for eight weeks, or the combination alone for Ledipasvir is minimally metabolised with most of the 12 weeks. There was a sustained virological response dose being excreted unchanged in the faeces. The in 94% of the patients who took the combination for median half-life is 47 hours. No dose adjustment is eight weeks (93% with ribavirin) compared with 95% required in patients with hepatic impairment. who took it for 12 weeks.3 An eight-week regimen The fixed-dose combination of ledipasvir and can therefore be considered in previously untreated sofosbuvir has mainly been studied in patients patients without cirrhosis who have pre-treatment viral with genotype 1 infection. Its approval is based on RNA concentrations below 6 million IU/mL. open-label clinical trials which assessed the virological ION-4 was an open-labelled study involving 335 response (see Table). A sustained virological patients who were infected with hepatitis C virus response was defined as a viral RNA in the patient’s and HIV. Using a 12-week regimen, a sustained serum below 25 IU/mL 12 weeks after the end of response against hepatitis C was achieved by 96% of treatment. However, the World Health Organization the patients. Results were similar irrespective of the has previously considered a sustained response to treatments used for HIV in the trial, and whether or be the absence of viral RNA six months after the end not the patients had cirrhosis.4 of treatment. Less than 1% of the patients treated with ledipasvir In ION-1, 865 previously untreated patients were and sofosbuvir had to stop treatment because of randomised to take the combination, with or without adverse effects. Without ribavirin, the most frequent ribavirin, in either 12- or 24-week regimens. There adverse events with the combination were fatigue, was a sustained viral response in 97–99% of the headache, nausea and insomnia. There are no human patients. This response was achieved by 94–100% data in pregnancy and lactation, but the combination of the patients who had cirrhosis (16% of the trial had no effect on fetal development in animal studies. participants).1 Drug interactions can occur with one or both The ION-2 trial used the same four treatment components of the combination, so it is best to check regimens as ION-1, but studied 440 patients who had the product information before prescribing. Its efficacy not responded to other treatments for genotype 1 could be reduced by inducers of P-glycoprotein infections. Approximately 20% of these patients had such as rifampicin and St John’s wort. There is a cirrhosis. Twelve weeks after completing 12 weeks potentially fatal interaction with amiodarone. Other of treatment, there was a virological response of interactions include digoxin, antiepileptic drugs, and 94–96%. In patients who were treated for 24 weeks a statins particularly rosuvastatin. There is no known viral RNA below 25 IU/mL was achieved in 99%. The interaction with oral contraception. response rate was significantly lower in patients with Resistance to ledipasvir can develop during treatment. cirrhosis who were treated for 12 weeks compared This should be considered in patients who do not with 24 weeks (82–86% vs 100%).2 have a sustained virological response. Table Efficacy of ledipasvir and sofosbuvir in hepatitis C Trial Patients Sustained virological response for patients taking 12-week regimens ‡ Ledipasvir/sofosbuvir Ledipasvir/sofosbuvir plus ribavirin ION-11 865 previously 99% (211/214) 97% (211/217) untreated patients ION-22 440 previously 94% (102/109) 96% (107/111) treated patients ION-33 647 previously 95% (206/216) - untreated patients without cirrhosis ION-44 335 patients 96% (322/335) - coinfected with HIV ‡ Primary outcome was the proportion of patients who had no quantifiable RNA in their sera 12 weeks after treatment 220 Full text free online at www.australianprescriber.com VOLUME 38 : NUMBER 6 : DECEMBER 2015 NEW DRUGS A once-daily, interferon-free treatment, which in Ponatinib is also indicated for those with Ph-positive most cases only needs to be taken for 12 weeks, acute lymphoblastic leukaemia who are resistant or that has very high efficacy is an advance.
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